Ipamorelin Research

Evidence

Ipamorelin mechanism of action

How ipamorelin acts at the GHSR-1a receptor, step by step, with each link in the pathway marked as established, indirectly supported or merely proposed.

By the Ipamorelin Research editorial team · Last reviewed · Scientific review: pending

Short answer

Ipamorelin binds GHSR-1a, the ghrelin receptor, on pituitary somatotroph cells. Receptor activation triggers intracellular signalling that causes those cells to release stored growth hormone, producing a single pulse that peaks about 40 minutes after dosing and then falls back to baseline. Growth hormone then acts on the liver to induce IGF-1 — but that last step is conditional, and in several ipamorelin studies growth hormone rose while IGF-1 did not move at all.

The pathway, step by step

Each step below is drawn only where an indexed study supports it. Selecting a step shows what was measured, in which species, and what kind of evidence supports it: green where ipamorelin itself was measured, amber where the support comes from a related compound or an indirect model, blue where study authors proposed rather than measured the link, and red where the chain stops.

GHSR-1a receptor and growth hormone explorer

Select any step. Every step states what kind of evidence supports it and in which model.

IpamorelinCirculationGHSR-1aAnterior pituitaryGq / PLC / Ca²⁺Anterior pituitaryGH releaseAnterior pituitaryGH pulseCirculationSelectivityCirculationIGF-1LiverFeedbackAnterior pituitaryGhrelin axisPeripheral tissuesGH-independentPeripheral tissuesHuman outcomesPeripheral tissues

Drag to pan, use the buttons to zoom, or move between steps with the arrow keys. Dashed lines mark a relationship that is inhibitory or that was specifically not observed.

What happens at the pituitary

In primary rat pituitary cells, ipamorelin released growth hormone with an EC50 of 1.3 ± 0.4 nmol/l and an efficacy of 85 ± 5% relative to GHRP-6 [Raun 1998]. Antagonist profiling in the same study placed that effect at a GHRP-like receptor rather than the GHRH receptor, and radio-competitive binding against radiolabelled ghrelin later confirmed GHSR1a binding for this peptide class [Ferro 2017]. After 21 days of dosing in young female rats, somatotroph ultrastructure was unchanged but secretion granule volume density increased [Jiménez-Reina 2002].

The shape of the growth hormone response

The human measurement is the important one here. In the 1999 dose-escalation study, every dose from 4.21 to 140.45 nmol/kg produced a single episode of growth hormone release, peaking at 0.67 hours and declining exponentially to negligible concentrations [Gobburu 1999]. The response was self-limiting at every dose tested, and the concentration producing half-maximal stimulation was 214 nmol/L. Between-subject variability was larger for the growth hormone response than for the pharmacokinetics.

The selectivity finding

In conscious swine, none of the secretagogues tested changed FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 raised plasma ACTH and cortisol; ipamorelin did not raise them significantly above the levels seen after GHRH stimulation, at doses more than 200-fold above its growth hormone ED50 [Raun 1998]. This is the finding that gives ipamorelin its reputation. It is worth being precise about what it is: an endocrine measurement in pigs after acute dosing, in a single study, by the group that developed the compound. It has not been replicated in humans, because no human study has measured ACTH or cortisol after ipamorelin.

Where the pathway becomes conditional

The step from growth hormone to IGF-1 is the one most often drawn as automatic, and it is not. Three indexed studies bear on it directly:

  • In adult female rats given ipamorelin for 15 days, longitudinal bone growth rose dose-dependently from 42 to 52 µm/day, while total IGF-1, IGF binding proteins and serum markers of bone formation and resorption were all unchanged [Johansen 1999].
  • In streptozotocin-diabetic mice, ipamorelin produced growth hormone of 150 ± 35 µg/L against 62 ± 11 µg/L in non-diabetic animals — more than double — yet hepatic IGF-1 mRNA, hepatic IGF-1 peptide and serum IGF-1 rose only in the non-diabetic animals [Johansen 2003].
  • In rats given methylprednisolone and then repeated intravenous ipamorelin over 10 days, IGF-1 did rise in parallel with reduced weight loss [Malmlöf 1999].

So the step can happen, and it can fail to happen, depending on the state of the liver and the dosing pattern. No human IGF-1 measurement after ipamorelin is indexed in this database at all.

Effects that do not go through growth hormone

GHSR-1a is not only a pituitary receptor, and not every effect of this compound class is downstream of growth hormone. In GH-deficient and GH-intact mice, ipamorelin increased relative body fat, serum leptin and food intake, while growth hormone itself decreased fat mass in the same experiment; the authors concluded that secretagogues increase body fat through GH-independent mechanisms that may include increased feeding[Lall 2001]. Separately, resection of the gastrointestinal tract attenuated the growth hormone response to GHRP-6 by 60 to 70% while leaving the GHRH response intact, which the authors read as evidence that endogenous ghrelin mediates part of this class's effect [Ahnfelt-Rønne 2001].

Where the mechanism stops being evidence

A mechanism is a reason to run a trial, not a substitute for one. The pathway above ends at a red step for that reason: the only randomised controlled human trial measured recovery of gut function after bowel resection and found no significant difference from placebo [Beck 2014]. Everything commonly claimed downstream of growth hormone in humans — muscle, recovery, fat, sleep, ageing — has no human ipamorelin measurement behind it. The claims page goes through each of those in turn.

Every step in the pathway, in words

  1. Step 1 · Circulation · Measured for ipamorelin

    Ipamorelin in the circulation

    Ipamorelin is a five-amino-acid peptide. Once it is in the bloodstream it circulates briefly: in healthy men its measured half-life was about two hours.

    Aib-His-D-2-Nal-D-Phe-Lys-NH2. In healthy male volunteers given 15-minute intravenous infusions, pharmacokinetics were dose-proportional with a terminal half-life of 2 hours, clearance 0.078 L/h/kg and steady-state volume of distribution 0.22 L/kg.

    Model: Healthy human volunteers; rats

    Supporting studies: Gobburu 1999 (grade B); Johansen 1998 (grade C)

    Leads to: GHSR-1a receptor binding (binds and activates); Effects that bypass growth hormone (raises food intake and fat in mice)

  2. Step 2 · Anterior pituitary · Measured for ipamorelin

    GHSR-1a receptor binding

    Ipamorelin acts on a receptor called GHSR-1a, the same receptor the body’s own hormone ghrelin uses. Blocking experiments showed ipamorelin works through this receptor and not through the separate GHRH receptor.

    GHSR-1a is a seven-transmembrane G-protein-coupled receptor. Pharmacological profiling with GHRP and GHRH antagonists showed ipamorelin stimulates GH release through a GHRP-like receptor rather than the GHRH receptor. Radio-competitive assay against radiolabelled ghrelin confirmed binding at GHSR1a for this peptide class.

    Model: Primary rat pituitary cells; receptor binding assay

    Supporting studies: Raun 1998 (grade C); Ferro 2017 (grade D)

    Leads to: Intracellular signalling (couples to Gq/11)

  3. Step 3 · Anterior pituitary · Indirect or related-compound evidence

    Intracellular signalling

    When the receptor is activated it sets off chemical messengers inside the cell, which is what triggers the cell to release its stored hormone.

    GHSR-1a couples to Gq/11, activating phospholipase C, inositol phosphate turnover and intracellular calcium mobilisation. Inositol phosphate turnover at human GHS-R 1A expressed in BHK cells was measured for a related secretagogue, and calcium mobilisation assays were used to characterise ghrelin-derived agonists at this receptor.

    Model: Transfected cell lines, with related ligands rather than ipamorelin

    Supporting studies: Hansen 1999 (grade C); Matsumoto 2001 (grade D)

    Leads to: Somatotroph GH release (triggers secretion)

  4. Step 4 · Anterior pituitary · Measured for ipamorelin

    Somatotroph GH release

    The pituitary gland contains cells that store growth hormone. Activating the receptor makes those cells release it.

    Ipamorelin released GH from primary rat pituitary cells with EC50 1.3 ± 0.4 nmol/l and Emax 85 ± 5% relative to GHRP-6. Chronic dosing in young female rats increased secretion granule volume density in somatotrophs without changing somatotroph ultrastructure or the proportion of GH-staining cell types.

    Model: Primary rat pituitary cells; rat pituitary histology

    Supporting studies: Raun 1998 (grade C); Jiménez-Reina 2002 (grade C)

    Leads to: A single pulse of growth hormone (releases GH into blood); Other pituitary hormones unchanged (without raising ACTH or cortisol)

  5. Step 5 · Circulation · Measured for ipamorelin

    A single pulse of growth hormone

    In healthy men, each infusion produced one burst of growth hormone that peaked after about 40 minutes and then fell back to negligible levels. It was a single pulse, not a sustained rise.

    In the human dose-escalation study, the time course of GH stimulation showed a single episode of GH release peaking at 0.67 hours with exponential decline to negligible GH concentrations at every dose tested. The concentration producing half-maximal GH stimulation was 214 nmol/L. Between-subject variability was larger for pharmacodynamic than pharmacokinetic parameters.

    Model: Healthy human volunteers (8 per dose level, 5 dose levels)

    Supporting studies: Gobburu 1999 (grade B)

    Leads to: Hepatic IGF-1 production (induces IGF-1, conditionally)

  6. Step 6 · Circulation · Measured for ipamorelin

    Other pituitary hormones unchanged

    Unlike some similar compounds, ipamorelin did not raise the stress hormones ACTH and cortisol in pigs, even at doses far above those needed for growth hormone release. This is the finding ipamorelin is best known for.

    In conscious swine, none of the secretagogues tested altered FSH, LH, PRL or TSH. GHRP-6 and GHRP-2 increased plasma ACTH and cortisol, whereas ipamorelin did not raise them significantly above levels observed following GHRH stimulation, at doses more than 200-fold above its GH ED50. The authors described ipamorelin as the first GHRP-receptor agonist with GH selectivity comparable to GHRH.

    Model: Conscious swine, acute dosing

    Supporting studies: Raun 1998 (grade C)

  7. Step 7 · Liver · Indirect or related-compound evidence

    Hepatic IGF-1 production

    Growth hormone normally tells the liver to make IGF-1. But this step is conditional: in several ipamorelin studies growth hormone went up while IGF-1 did not move at all.

    GH acts on hepatic GH receptors to induce IGF-I transcription. In diabetic mice, ipamorelin provocation produced higher GH than in non-diabetic animals, yet hepatic IGF-I mRNA and peptide and serum IGF-I rose only in the non-diabetic animals, demonstrating hepatic GH resistance. In adult female rats given ipamorelin for 15 days, longitudinal bone growth rose dose-dependently while total IGF-I and IGF binding proteins were unchanged. In glucocorticoid-treated rats given repeated intravenous ipamorelin over 10 days, IGF-I did rise.

    Model: Rats and mice; no human IGF-1 measurement is indexed

    Supporting studies: Johansen 2003 (grade C); Johansen 1999 (grade C); Malmlöf 1999 (grade C)

    Leads to: Negative feedback on the axis (feeds back on the pituitary); Clinical outcomes in people (no human outcome evidence)

  8. Step 8 · Anterior pituitary · Proposed by study authors

    Negative feedback on the axis

    The body limits its own growth hormone. Repeated stimulation produced a slightly smaller response over time in rats, which is consistent with the system regulating itself.

    After 15 days of ipamorelin in adult female rats, the plasma GH response to a provocative dose of ipamorelin was marginally reduced (P < 0.03) while the response to GHRH was unchanged and pituitary GH content was unaffected. The self-limiting single-pulse pattern seen in humans is consistent with intact somatostatin and IGF-1 feedback, but feedback mediators were not measured in these studies.

    Model: Adult female rats; inferred from the human pulse shape

    Supporting studies: Johansen 1999 (grade C); Gobburu 1999 (grade B)

    Leads to: Somatotroph GH release (limits further release)

  9. Step 9 · Peripheral tissues · Indirect or related-compound evidence

    Endogenous ghrelin involvement

    Some of the growth hormone effect of this family of compounds may come indirectly, by involving the stomach where the body makes its own ghrelin. This was shown for related compounds, not for ipamorelin.

    Whole-body autoradiography showed NN703 and GHRP-6 accumulate in the glandular stomach of rats, and resection of the gastrointestinal tract attenuated the GH response to GHRP-6 by 60–70% while leaving the GHRH response intact. The authors interpreted this as a role for endogenous ghrelin in mediating part of the GH-releasing effect of growth hormone-releasing peptides.

    Model: Rats, using NN703 and GHRP-6 rather than ipamorelin

    Supporting studies: Ahnfelt-Rønne 2001 (grade C)

    Leads to: GHSR-1a receptor binding (may contribute (related compounds))

  10. Step 10 · Peripheral tissues · Measured for ipamorelin

    Effects that bypass growth hormone

    Not everything this compound class does goes through growth hormone. In mice, secretagogues increased food intake and body fat even where growth hormone itself reduced fat.

    In GH-deficient (lit/lit) and GH-intact mice, ipamorelin increased fat pad weights relative to body weight and, with GHRP-6, increased relative body fat measured by DEXA in GH-intact mice. GH itself decreased relative fat mass in lit/lit mice. Secretagogue treatment, but not GH, increased serum leptin and food intake. The authors concluded secretagogues increase body fat by GH-independent mechanisms that may include increased feeding.

    Model: Mice, 2 to 9 weeks of subcutaneous dosing

    Supporting studies: Lall 2001 (grade C)

  11. Step 11 · Peripheral tissues · Not demonstrated for ipamorelin

    Clinical outcomes in people

    This is where the pathway stops. The one randomised human trial measured recovery of gut function after bowel surgery and found no significant difference from placebo. No human trial has measured muscle, fat, recovery or ageing.

    The single randomised controlled human trial (NCT00672074, n = 117) compared intravenous ipamorelin 0.03 mg/kg twice daily with placebo after bowel resection. Median time to first tolerated solid meal was 25.3 h against 32.6 h for placebo (P = 0.15); the authors reported no significant differences in the key and secondary efficacy analyses. A larger four-arm dose-finding trial (NCT01280344, n = 320) completed in May 2014 with no results posted to the registry and no publication found. No indexed human study measured body composition, muscle strength, athletic recovery, sleep or any ageing endpoint.

    Model: One randomised controlled trial, in postoperative ileus

    Supporting studies: Beck 2014 (grade A)

References

  1. Raun K, Hansen BS, Johansen NL et al. (1998). Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. PubMed 9849822 · doi:10.1530/eje.0.1390552[Animal, grade C]
  2. Gobburu JV, Agersø H, Jusko WJ et al. (1999). Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. PubMed 10496658 · doi:10.1023/a:1018955126402[Human, grade B]
  3. Hansen BS, Raun K, Nielsen KK et al. (1999). Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol. PubMed 10427162 · doi:10.1530/eje.0.1410180[Animal, grade C]
  4. Matsumoto M, Kitajima Y, Iwanami T et al. (2001). Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Biochem Biophys Res Commun. PubMed 11396951 · doi:10.1006/bbrc.2001.5014[In vitro, grade D]
  5. Jiménez-Reina L, Cañete R, de la Torre MJ et al. (2002). Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histol Histopathol. PubMed 12168778 · doi:10.14670/HH-17.707[Animal, grade C]
  6. Ahnfelt-Rønne I, Nowak J, Olsen UB (2001). Do growth hormone-releasing peptides act as ghrelin secretagogues?. Endocrine. PubMed 11322495 · doi:10.1385/ENDO:14:1:133[Animal, grade C]
  7. Johansen PB, Segev Y, Landau D et al. (2003). Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue. Exp Diabesity Res. PubMed 14630569 · doi:10.1155/EDR.2003.73[Animal, grade C]
  8. Johansen PB, Nowak J, Skjaerbaek C et al. (1999). Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res. PubMed 10373343 · doi:10.1054/ghir.1999.9998[Animal, grade C]
  9. Malmlöf K, Johansen PB, Haahr PM et al. (1999). Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats. Growth Horm IGF Res. PubMed 10629165 · doi:10.1054/ghir.1999.0128[Animal, grade C]
  10. Lall S, Tung LY, Ohlsson C et al. (2001). Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochem Biophys Res Commun. PubMed 11162489 · doi:10.1006/bbrc.2000.4065[Animal, grade C]
  11. Ferro P, Krotov G, Zvereva I et al. (2017). Structure-activity relationship for peptídic growth hormone secretagogues. Drug Test Anal. PubMed 26811125 · doi:10.1002/dta.1947[In vitro, grade D]
  12. Beck DE, Sweeney WB, McCarter MD et al. (2014). Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. PubMed 25331030 · doi:10.1007/s00384-014-2030-8[Human, grade A]